Computational insights into Caenorhabditis elegans vulval development

doi:10.1073/pnas.0409433102

Computational insights into Caenorhabditis elegans vulval development

^*Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 76100, Israel; ^‡Department of Biology, New York University, New York, NY 10003-6688; and ^§Department of Genetics, Yale University School of Medicine, New Haven, CT 06520-8005

Communicated by Richard M. Karp, International Computer Science Institute, Berkeley, CA, December 17, 2004 (received for review July 22, 2004)

Abstract

Studies of Caenorhabditis elegans vulval development provide a paradigm for pattern formation during animal development. The fates of the six vulval precursor cells are specified by the combined action of an inductive signal that activates the EGF receptor mitogen-activated PK signaling pathway (specifying a primary fate) and a lateral signal mediated by LIN-12/Notch (specifying a secondary fate). Here we use methods devised for the engineering of complex reactive systems to model a biological system. We have chosen the visual formalism of statecharts and use it to formalize Sternberg and Horvitz's 1989 model [Sternberg, P. W. & Horvitz, H. R. (1989) Cell 58, 679–693], which forms the basis for our current understanding of the interaction between these two signaling pathways. The construction and execution of our model suggest that different levels of the inductive signal induce a temporally graded response of the EGF receptor mitogen-activated PK pathway and make explicit the importance of this temporal response. Our model also suggests the existence of an additional mechanism operating during lateral specification that prohibits neighboring vulval precursor cells from assuming the primary fate.

Footnotes

↵ † To whom correspondence should be addressed. E-mail: jasmin.fisher{at}weizmann.ac.il.
Author contributions: J.F., N.P., and D.H. designed research; J.F. and N.P. performed research; J.F., N.P., E.J.A.H., M.J.S., and D.H. analyzed data; and J.F., E.J.A.H., M.J.S., and D.H. wrote the paper.
Abbreviations: VPC, vulval precursor cell; AC, anchor cell.
↵ ¶ In some animals, P3.p is not a member of the VPC equivalence group but instead fuses earlier with the hypodermal syncytium (16, 17).
↵ ∥ The VulMutation condition can be thought of as a disjunction over these five genes.
↵ ** The number of ACs was represented as present or absent, and VPC fates were categorized as 1⁰, 2⁰, or 3⁰, not by specific lineages. The genetic conditions that were tested did not distinguish the individual genotypes but instead were represented as the class of mutation (Muv, Vul, and lin-12). These abstractions are similar to those used in Sternberg and Horvitz (13).